Estuaries often show regions in which Chlorophyll-a (Chl-a) accumulates. The location and magnitude corresponding to such accumulation result from a complex interplay between processes such as river flushing, salinity, nutrients, grazing on phytoplankton, and the light climate in the water column. An example is the multi-annual evolution of the estuary-scale Chl-a distribution in the Scheldt estuary (Belgium/Netherlands) in spring. From 2004–2007, we observed a limited spring bloom in the brackish region (km 60–90 from the mouth, salinity ∼ 1–10 ppt). This bloom intensified in 2008–2014 and disappeared after 2015. This multi-annual evolution of Chl-a has been hypothesized to be linked to simultaneous multi-annual trends in the suspended particulate matter (SPM) distribution in summer and winter between 1995–2015 and the improvement of the water quality (e.g., reduction of ammonium), which affects grazing on phytoplankton by zooplankton. However, this hypothesis has not been systematically investigated. In this contribution, we apply a modeling approach in which observations are the core. We first analyze multi-annual in situ observations covering the full estuary. These observations include the SPM concentration, zooplankton abundance, and other variables affecting the Chl-a concentration. They show a multi-annual estuary-scale evolution not only in the SPM distribution but also in zooplankton abundance, freshwater discharge, and phytoplankon photosynthetic characteristics. Next, we apply a model approach that consists of an extensive sensitivity study and four model scenarios that are supported by these observations to constrain the processes and corresponding parameter variability that may have caused the observed change in Chl-a. Our results suggest that a change in SPM alone cannot explain the Chl-a observations. Instead, a multi-annual change in mortality rate, which we can attribute to both grazing by zooplankton and phytoplankton community (i.e., mortality dependence on salinity), may explain the multi-annual estuary-scale evolution of Chl-a in spring. Different model parameter choices may thus lead to similar model results (equifinality). Our results highlight that insight into the zooplankton dynamics and phytoplankton community characteristics is essential to understand the phytoplankton (cf. Chl-a) dynamics in the Scheldt estuary and that additional data regarding mortality and grazing rates is required to further constrain the model parameters.